Anti-GARP Chimeric Antigen Receptor T Cell Therapy for the Treatment of Recurrent Grade III or IV Gliomas

PRIMARY OBJECTIVE:

I. To assess the safety and feasibility of a CAR T targeting GARP for glioma by defining rate, frequency, and severity of dose limiting toxicities (DLT) following intracavity administration to patients with recurrent glioma, to determine recommended phase II dose (RP2D).

SECONDARY OBJECTIVES:

I. To describe the adverse event profile of anti-GARP CAR T cell therapy. II. To describe the cytokine levels and immunophenotype in cerebrospinal fluid (CSF) during and following anti-GARP CAR T cell therapy.

III. To describe the duration of anti-GARP CAR T cell persistence and phenotype in CSF.

IV. To describe anti-tumor activity of anti-GARP CAR T cell therapy based on objective response rate (ORR), as measured by established radiological criteria.

V. To estimate the progression-free survival (PFS) and overall survival (OS) of patients receiving anti-GARP CAR T cell therapy.

VI. For research participants with tumor specimens from primary resections and/or autopsy, describe GARP expression levels pre- and post-treatment and correlate with outcomes.

VII. To describe the frequency and phenotype of anti-GARP CAR T cells and describe GARP expression in resected post-treatment tumor tissue at progression (for patients in whom surgical resection is indicated).

EXPLORATORY OBJECTIVES:

I. To assess peripheral blood (mononuclear cells, plasma) and CSF for biomarkers that may be associated with response to anti-GARP CAR T cell therapy.

II. To assess archival tissues (primary resection), recurrent tumor, and/or autopsy specimens for biomarkers that may be associated with response to anti-GARP CAR T cell therapy.

III. To assess baseline genetic markers that may be associated with response to anti-GARP CAR T cell therapy.

OTHER EFFICACY OBJECTIVES:

I. Best overall response, determined via response assessment in neuro-oncology (RANO) criteria.

II. Clinical benefit rate that includes all subjects receiving 5 doses of anti-GARP CAR T cell therapy who demonstrate a complete response (CR), partial response (PR), or stable disease (SD) of at least 6 months duration.

III. Duration of response, calculated as the time from which a response is first observed (CR or PR) until progression or death, whichever occurs first.

IV. Overall survival (OS), calculated from first administration of study drug until death for up to two years after receiving the drug.

OUTLINE: This is a dose-escalation study.

Patients undergo apheresis on day -14 and undergo surgery and placement of CSF reservoir on day 0. Patients receive anti-GARP CAR T intracavitary infusion on day 14, 21, 28, 35 and 42 in the absence of disease progression or unacceptable toxicities. Additionally, patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) at screening and collection of CSF and blood samples, lumbar puncture, chest x-ray and magnetic resonance imaging (MRI) throughout the study.

After completion of study treatment, patients are followed up at 2 weeks then at 3, 4, 6, 8, 12 and 24 months then annually for at least 15 years.

Inclusion criteria

• Patients are ≥ 18 years old
• Capacity to understand and willingness to provide written informed consent
• Diagnosis or clinical suspicion of recurrent malignant glioma, including:

• History of high-grade glioma (World Health Organization [WHO] grade III or IV), or
• Prior, histologically-confirmed diagnosis of grade II glioma with new radiographic findings consistent with a high-grade glioma
• Imaging and/or histopathological confirmation of recurrent disease, or verification of "high risk" histology confirmed by a biopsy with measurable disease by the Radiologic Assessment in Neuro-Oncology (RANO) criteria
• Patient has unifocal disease in one hemisphere and is supratentorial. Lesion and edema can not be located in eloquent locations (e.g., brainstem, pre-/post-central gyrus, visual cortex) or within 2 gyri of motor strip.
• If on steroids such as dexamethasone, must be on a low dose (≤ 4mg per day) at the time of treatment, and not at an ascending dosage schedule at time of enrollment/leukapheresis

• Prior to apheresis and treatment 1 a 2- week washout should be observed
• Subjects must not have received bevacizumab therapy and are not planned to start such therapy
• Karnofsky performance score (KPS) ≥ 60
• Subject is a surgical candidate for surgery for malignant glioma with the intent of resecting >80-90% of the tumor as the ideal treatment option
• White blood cells (WBC) > 4,000 cells/uL
• Hemoglobin (Hgb) > 7 gm/dL
• Platelets (Plt) > 100/dL
• Serum creatinine ≤ 1.5 x institutional upper limit of normal
• Liver function tests within 1.5 x institutional upper limit of normal
• Women of reproductive potential must have a negative pregnancy test within 7 days of study start. All patients of reproductive potential must use a physician-approved contraceptive and refrain from sperm donation for at least two weeks prior, during, and six months after final T cell infusion. Women must refrain from breastfeeding for six months after final T cell infusion
• Sufficient venous access, to be confirmed prior to apheresis
• Life expectancy of greater than 12 weeks
• PI clinical judgement of patients who will likely complete the trial and are able to maintain stable neurologic symptoms during intervention period

Exclusion criteria

• Patients who have a history of malignancy other than the glioma under investigation in this study, except patients with the following malignancies/treatment characteristics, who are eligible at the investigator's discretion:

• Patients with a history of malignancy that has been treated with curative intent at least 2 years prior to screening and with no evidence of relapse, if no concurrent anti-cancer therapy (except hormonal therapy) is being given
• Patients with a history of malignancy with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%) such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer
• Patients who have prostate cancer with no evidence of metastatic disease and are not on active therapy, except anti-androgen therapy
• History of autoimmune disease, or other diseases require long-term administration of high-dose steroids [> 10 mgs/day] or immunosuppressive therapies

• Research participants who received steroids must have either received their last dose of steroids 7 days or more prior to apheresis or have dosage tapered to < 2mg/kg/day
• Patients being treated concurrently (within 14 days prior to study enrollment) with any other investigational agent

• Examples of other investigational agents that would be exclusionary include supportive care agents
• Patients receiving anti-cancer agents such as chemotherapy (e.g., temozolomide) must stop treatment 14 days prior to undergoing apheresis and remain off therapy throughout the duration of CAR T therapeutic intervention
• Patients with active fungal, bacterial, viral, or other infection that requires intravenous antimicrobials

• Prophylactic antimicrobials are allowed
• Patients with active invasive fungal infection should be excluded even if the treatment is oral antimicrobials
• History of allergy to study products/diluents/emulsions
• Recent history (within last 3 months) of uncontrolled seizures